Background: CDK4/6i in combination with endocrine therapy (ET) are a standard of care in hormone receptor positive, HER2 negative MBC. Palbociclib, ribociclib and abemaciclib have all been approved and while efficacy appears similar, differences in safety and tolerability are apparent. Here we quantify TRAEs comparing the 3 CDK4/6i in a network meta-analysis. Methods: We searched PubMed and ASCO and ESMO proceedings to identify randomized trials (RCT) of CDK4/6i. Data on common and serious TRAE were extracted for each approved CDK4/6i. The odd ratio (OR) for each TRAE and the hazard ratio (HR) for progression-free survival (PFS) were calculated relative to ET alone. A network meta-analysis was then performed for each ET backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib. Results: 7 RCT were included in the analysis and comprised 2715 patients receiving CDK4/6i (palbociclib: 789 patients; ribociclib: 1153 patients; abemaciclib: 773 patients). In 4 RCT (1440 patients) ET backbone was an AI and in 3 RCT (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed lower grade 3-4 hematological toxicity, but higher GI toxicity (see table). Treatment discontinuation was higher with abemaciclib than other CDK4/6i. Efficacy of the 3 CDK4/6i was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 1.00 and for abemaciclib 1.04. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively. Conclusions: The three approved CDK4/6i show comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to gastro-intestinal toxicity.